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T. Takahashi



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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.02 - Thoracic Radiotherapy With or Without Concurrent Daily Low-Dose Carboplatin in Elderly Patients With Locally Advanced Non-small Cell Lung Cancer: Updated Results of the JCOG0301 and Pooled Analysis With the JCOG9812 Trial. (ID 734)

      10:30 - 12:00  |  Author(s): T. Takahashi

      • Abstract
      • Presentation
      • Slides

      Background
      The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

      Methods
      The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

      Results
      In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

      Conclusion
      This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-008 - Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy (ID 830)

      09:30 - 16:30  |  Author(s): T. Takahashi

      • Abstract

      Background
      To evaluate the prognostic factors associated with overall survival in patients with brain metastasis from non-small cell lung cancer(NSCLC) who received whole-brain radiotherapy (WBRT).

      Methods
      From September 2002 to December 2010, 257 patients with brain metastasis from NSCLC who received WBRT. Those who had undergone craniotomy or stereotactic radiotherapy before WBRT and those with leptomeningeal metastasis were excluded. The prognostic factors evaluated for overall survival were; gender, neurological deficit, histology, epidermal growth factor receptor (EGFR) mutation status, previous cytotoxic chemotherapy, previous EGFR tyrosine kinase inhibitor (TKI) treatment, RTOG-recursive partitioning analysis (RPA) (age,Karnofsy Performance Scale [KPS], primary tumor control), and diagnosis-specific graded prognostic assessment (DS-GPA)(age, KPS, extra cranial control, number of lesions). All factors with a Pvalue < 0.05 at univariate analysis were entered into a multivariate analysis using Cox regression with confidential interval of 99%.

      Results
      At the time of analysis, 225 patients (88%) died, 14 patients (5%) were alive, and 18 patients (7%) were lost to follow-up. The median follow-up time was 16.2 months. The median survival time (MST) was 5.6 months and 1-year survival rate was 28.6%. The MST according to gender, neurological deficit, histology, EGFR mutation status, previous chemotherapy, previous EGFR-TKI treatment, RPA class, and DS-GPA were shown in Table 1. In univariate analysis, the significant prognostic factors were; gender (P=0.0002), neurological deficits (P<0.0001), histology (P<0.0001), previous chemotherapy (P=0.0463), EGFR mutation (P=0.0236), RPA class (P<0.0001) and DS-GPA (P=0.0003). In multivariate analysis, RPA class (I and II vs III,KPS>70 vs <70), histology (adenocarcinoma vs non-adenocarcinoma) and previous chemotherapy (none vs present) were found to be significant prognostic factors (Table 2).Figure 1 Figure 2

      Conclusion
      RPA class I or II (KPS>70), adenocarcinoma and no previous chemotherapy were associated with longer survival. These factors should be taken into account for decision-making in an attempt to find optimal treatment for patients with brain metastasis.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-006 - Long-term results of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (ID 1371)

      09:30 - 16:30  |  Author(s): T. Takahashi

      • Abstract

      Background
      Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). S-1 has been shown to be significant efficacious for treating advanced NSCLC. Our previous phase II study reported short-term outcomes of cisplatin (CDDP)/S-1 chemoradiotherapy. Because CDDP/S-1 chemoradiotherapy is considered to have advantages over others in overall survival (OS) and toxicity, we analyzed its long-term outcomes by following up patients included in the phase II study.

      Methods
      Forty-eight patients (aged <75 years) with unresectable stage III NSCLC were evaluated. They were treated with CDDP (60 mg/m[2] on day 1) intravenously and oral S-1 (40 mg/m[2] twice daily on days 1–14); this regimen was repeated every 4 weeks for four cycles. A 60-Gy thoracic radiation dose was delivered in 30 fractions beginning on day 2.

      Results
      After a median follow-up of 6.3 years (range, 5.7–7.4 years), the median OS was 2.8 years [95% confidence interval (CI); 1.04–4.63 years], and the 3- and 5-year OS rates were 49.7% (95% CI: 35.6%–63.8%) and 33.0% (95% CI: 20.0%–46.6%), respectively. Out of the several variables evaluated as predictors of OS, including gender, age, stage, histology, and performance status (PS), only PS proved to be a statistically significant predictor in both univariate and multivariate analyses.

      Conclusion
      CDDP/S-1 concurrent thoracic radiotherapy is clinically feasible and highly efficacious. Despite our relatively small sample size, the benefits of this regimen revealed in this study warrant further research.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-021 - The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harbouring mutations of the epidermal growth factor receptor. (ID 1367)

      09:30 - 16:30  |  Author(s): T. Takahashi

      • Abstract

      Background
      For patients with postoperative recurrent non-small cell lung cancer (NSCLC) harbouring mutations of the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitor, such as gefitinib, is frequently used in clinical practice, in accordance with the treatment for patients with stage IV NSCLC. However, it is unclear whether there is a difference in effect of gefitinib between patients with postoperative recurrent NSCLC and patients with stage IV NSCLC, harbouring EGFR mutations.

      Methods
      We reviewed consecutive patients with postoperative recurrent or stage IV (at diagnosis) NSCLC harbouring EGFR mutations, who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012. The clinical data of the patients were obtained from their medical records, and retrospectively reviewed. The baseline patient characteristics, response to gefitinib, and survival were compared between patients with postoperative recurrent NSCLC (postoperative group) and patients with stage IV NSCLC at diagnosis (stage IV group). Patients were not included if they had received other EGFR tyrosine kinase inhibitors before administration of gefitinib.

      Results
      A total of 169 patients met the eligibility criteria for this study (postoperative group; 50, stage IV group; 119). The baseline characteristics (sex, age, histology, EGFR mutations status, prior cytotoxic chemotherapy) were well balanced between both groups, with the exception of performance status (PS). Patients in postoperative group had better PS than those in stage IV group (p = 0.044). At the start of treatment with gefitinib, bone and liver metastases were more common in stage IV group (p = 0.002 and p = 0.032), and pulmonary metastases were more common in postoperative group (p = 0.004). There was no significant difference in number of metastatic sites between two groups. The response rate of gefitinib in postoperative group was similar to that in stage IV group (58 vs 61%, p = 0.685). In contrast, progression free survival (PFS) (median PFS 16.7 vs 9.8 months, p < 0.001) and overall survival (OS) (median OS 63.3 vs 23.9 months, p < 0.001) were significantly longer in postoperative group than in stage IV group. Additionally, postoperative recurrent disease, PS (0-1) and single metastatic site were independent prognostic factors in the multivariate analysis of survival.

      Conclusion
      PFS and OS were superior in patients with postoperative recurrent NSCLC harbouring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest, postoperative recurrent disease may be considered to be a stratification factor in clinical trial for NSCLC with EGFR mutations.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-012 - Pharmacogenetic study of Japanese patients with advanced non-squamous non-small cell lung cancer treated with pemetrexed plus cisplatin (ID 1407)

      09:30 - 16:30  |  Author(s): T. Takahashi

      • Abstract

      Background
      Pemetrexed (PEM) inhibits multiple enzymes in the folate (F) pathway. Several studies show that genetic polymorphisms in these enzymes influence the efficacy and toxicity of PEM. We aimed to investigate the relationship between genetic polymorphisms associated with the F pathway and clinical outcomes of Japanese patients with advanced non-squamous non-small cell lung cancer (NSQ-NSCLC) treated with PEM plus cisplatin (CIS).

      Methods
      We analyzed 34 polymorphisms in 14 genes associated with the F pathway in NSQ-NSCLC patients treated with PEM plus CIS: ABCC11, ADA, ATIC, DHFR, ERCC1, FPGS, GGH, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS. These polymorphisms were compared with clinical outcomes such as response, toxicity, and progression-free survival (PFS) using Pearson’s χ[2] test and the log-rank test.

      Results
      All 56 patients were Japanese, with a median age of 62 years; 57.1% were male, 96.4% had an Eastern Cooperative Oncology Group Performance Status of 0–1, 96.4% had stage IV disease, and 94.6% had adenocarcinoma. The response rate, disease control rate, and median PFS were 32.2%, 78.6%, and 4.7 months, respectively. Of the 38 polymorphisms tested, none were associated with response or toxicity, but 2 single nucleotide polymorphisms (SNPs) (in the gamma-glutamyl hydrolase [GGH 452C>T] and methionine synthase [MTR 2756A>G] genes) were significantly associated with PFS. Patients harboring the GGH-C452C variant had significantly longer PFS (5.6 vs 2.8 months; p < 0.0001) than those with the C452T or T452T variants. Further, patients harboring the MTR-A2756A variant had significantly longer PFS (5.3 vs 3.7 months; p = 0.036) than those with the A2756G variant. In addition, among patients with the GGH-C452C variant, those harboring the MTR-A2756A variant had significantly longer PFS (5.9 vs 4.3 months; p = 0.044) than those with the A2756G variant.

      Conclusion
      SNPs in GGH and MTR seem to predict differences in PFS in NSQ-NSCLC patients treated with PEM plus CIS, and a combination of these 2 SNPs may predict differences in PFS more accurately. These results should be validated in larger, adequately designed prospective studies.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 16:30  |  Author(s): T. Takahashi

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
      　cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with　CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.